Major Cardiovascular Events in Hypertensive Patients Randomized to - - PowerPoint PPT Presentation

Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone

Final Results From The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI)

• Hypertension. 2003;42:239-246

ALLHAT

Antihypertensive Trial Design

• Randomized, double-blind, multi-center

clinical trial

• Determine whether occurrence of fatal CHD or

nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic

• 42,418 high-risk hypertensive patients ≥ 55

years

ALLHAT

Secondary Objectives: Subgroups

Pre-specified

–Age 65+ –Women –African-Americans –Diabetic patients

Post-hoc

–Baseline CHD

ALLHAT

Secondary Outcomes

• All-cause mortality
• Stroke
• Combined CHD – nonfatal MI, CHD death, coronary

revascularization, hospitalized angina

• Combined CVD – combined CHD, stroke, lower

extremity revascularization, treated angina, fatal / hospitalized / treated non-hospitalized CHF, hospitalized or outpatient PAD

• Other clinical outcomes – renal (reciprocal serum

creatinine, ESRD, estimated GFR) and cancer

ALLHAT

Sites in ALLHAT

• 623 clinical sites
• United States, Canada, Puerto Rico, US

Virgin Islands

• VA, private & group general medicine

practices, community health centers, HMOs, specialty practices

• Variety of research experience

ALLHAT

Inclusion Criteria for Antihypertensive Trial

• Age/sex: men and women aged > 55 years
• BP eligibility:

–Untreated systolic and/or diastolic hypertension (≥

140/90 mm Hg but ≤ 180/110 mm Hg at two visits)

–Treated hypertension

• ≤ 160/100 mm Hg on 1-2 antihypertensive drugs at Visit 1
• ≤ 180/110 mm Hg at Visit 2, when medication may have been

partially withdrawn

–No washout period was required in ALLHAT. ALLHAT

ALLHAT Inclusion Criteria: Risk Factors

At least one of the following:

• Myocardial infarction or stroke: at least 6

months old, or age-indeterminate

• History of revascularization procedure
• Major ST segment depression or T-wave

inversion

• Other documented ASCVD

ALLHAT

ALLHAT Inclusion Criteria: Risk Factors

At least one of the following (cont.)

• Type 2 diabetes mellitus
• HDL cholesterol < 35 mg/dL on any 2 or

more determinations in past 5 years

• Left ventricular hypertrophy (past 2 years)

– ECG, or echo (septum + posterior wall

thickness ≥ 25 mm)

• Current cigarette smoking

ALLHAT

Major Exclusion Criteria

• MI, stroke, or angina within 6 months
• Symptomatic CHF or ejection fraction <

35%

• Known renal insufficiency - creatinine ≥ 2

mg/dL

• Requiring diuretics, CCB, ACEI, or alpha

blockers for reasons other than hypertension

ALLHAT

Sample Size Assumptions & Statistical Methods

• 83% power to detect 16% reduction in risk for primary
• utcome

– 99% power to detect 20% reduction with the observed event rate

• 2-sided α=.0178 (z=2.37) accounts for multiple comparisons
• Analysis according to “intent to treat”
• Cumulative event rates – Kaplan-Meier
• Differences between event curves - Log-rank tests & Cox

proportional hazards (PH) model

• PH assumption tested by log-log plots, tests with treatment

by time interaction

– If violated, 2 x 2 table used

ALLHAT

Randomized Design of ALLHAT

High-risk hypertensive patients Consent / Randomize Amlodipine Chlorthalidone Doxazosin Lisinopril Eligible for lipid- lowering Not eligible for lipid-lowering Consent / Randomize Pravastatin Usual care Follow until death or end of study (4-8 yr, ave 6 yr).

ALLHAT

Step 1 Treatment Protocol

Step 1 Agent Initial Dose* Dose 1* Dose 2* Dose 3* Chlorthalidone 12.5 12.5 12.5 25 Amlodipine 2.5 2.5 5 10 Lisinopril 10 10 20 40 Doxazosin 1 2 4 8 * mg/day

ALLHAT

Step 2 Agents: Dose 1* Dose 2* Dose 3* Reserpine 0.05 qd

• r 0.1 qod

0.1 qd 0.2 qd Clonidine (oral) 0.1 bid 0.2 bid 0.3 bid Atenolol 25 qd 50 qd 100 qd Hydralazine 25 bid 50 bid 100 bid

*All doses in mg

Step 3 Agent:

ALLHAT Step Up Treatment Protocol

Safety Outcomes

• Angioedema
• Hospitalization for gastrointestinal

bleeding

– Records from the VA hospitalization database – Records from the Center for Medicare & Medicaid Services (CMS) database (participants age 65 or older)

ALLHAT

Decision to Drop an ALLHAT Arm

• January 24, 2000 – NHLBI Director accepts

the recommendation of an independent review group to terminate doxazosin arm

– Futility of finding a significant difference for primary outcome – Statistically significant 25 percent higher rate of major secondary endpoint, combined CVD

• utcomes

ALLHAT

Baseline Characteristics

Chlorthalidone 15,255 Doxazosin 9,061 Mean SBP/DBP 146 / 84 146 / 84 Treated, % 90 90 67 36 46 22 ASCVD, % 46 46 36 Mean age, y 67 Black, % 35 Women, % 47 Current smoking % 22 Type 2 diabetes, % 36

ALLHAT

On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group

0.0 20.0 40.0 60.0 80.0 100.0 %

Chlor 88.2 87.0 86.0 84.8 Dox 81.3 78.3 75.6 74.0 12M 24M 36M 48M

ALLHAT

Full Crossovers by Antihypertensive Treatment Group

0.0 5.0 10.0 15.0 20.0 25.0 %

Chlor 0.4 0.6 1.0 1.1 Dox 4.9 6.6 9.0 10.2 12M 24M 36M 48M Chlorthalidone: not on assigned medicine or open- label diuretic, but on open-label alpha-blocker Doxazosin: not on assigned medicine or open-label alpha-blocker, but on open-label diuretic

ALLHAT

SBP Results by Treatment Group

130 135 140 145 150 6 12 18 24 30 36 42 48 Months mm Hg BP Chlorthalidone Doxazosin

ALLHAT

BL 6M 1Y 2Y 4Y C 146.2 138.2 136.7 135.8 135.3 D 146.3 141.1 139.8 138.1 137.5

DBP Results by Treatment Group

70 75 80 85 90 6 12 18 24 30 36 42 48 Months mm Hg BP Chlorthalidone Doxazosin

ALLHAT

BL 6M 1Y 2Y 4Y C 84 80.1 79.2 78.2 76.4 D 83.9 80 79.3 78.2 76.4

Vital Status by Antihypertensive Treatment Group ALLHAT

Chlorthalidone Doxazosin N 15,255 9,061 Lost to follow-up 545 (3.6%) 361 (4.0%) Deaths 1,258 (8.2%) 769 (8.5%) Observed / expected person-years 95% 95%

Combined CVD Event Rate Years to Combined CVD Event 1 2 3 4 5 .1 .2 .3 .4

Combined CVD Rates by ALLHAT Treatment Group

RR (95% CI) p value D/C 1.20 (1.13 – 1.27) <0.001

ALLHAT

Chlorthalidone Doxazosin

Favors Doxazosin Favors Chlorthalidone 0.33 0.50 1 2 3 No CHD 1.24 (1.15, 1.34) CHD 1.14 (1.04, 1.25) Treated 1.18 (1.11, 1.26) Untreated 1.39 (1.14, 1.70) Nondiabetic 1.19 (1.10, 1.28) Diabetic 1.22 (1.11, 1.33) Non-Black 1.16 (1.09, 1.25) Black 1.28 (1.16, 1.42) Women 1.17 (1.07, 1.29) Men 1.21 (1.13, 1.30) Age >= 65 1.23 (1.14, 1.32) Age < 65 1.15 (1.04, 1.27) Total 1.20 (1.13, 1.27) No CHD CHD 1.14 (1.04, 1.25) Treated 1.18 (1.11, 1.26) Untreated 1.39 (1.14, 1.70) Nondiabetic 1.19 (1.10, 1.28) Diabetic 1.22 (1.11, 1.33) Non-Black 1.16 (1.09, 1.25) Black 1.28 (1.16, 1.42) Women 1.17 (1.07, 1.29) Men 1.21 (1.13, 1.30) Age >= 65 1.23 (1.14, 1.32) Age < 65 1.15 (1.04, 1.27) Total 1.20 (1.13, 1.27)

RR and 95% CI for Combined CVD

ALLHAT

Cumulative HF Rate Years to HF 1 2 3 4 5 .05 .1 .15

Heart Failure Rates by ALLHAT Treatment Group

RR (95% CI) p value D/C 1.80 (1.61- 2.02) <0.001

ALLHAT

Chlorthalidone Doxazosin

Favors Doxazosin Favors Chlorthalidone 0.33 0.50 1 2 3 No CHD 1.91 (1.64, 2.22) CHD 1.75 (1.46, 2.11) Treated 1.87 (1.66, 2.11) Untreated 1.54 (0.98, 2.42) Nondiabetic 1.88 (1.60, 2.20) Diabetic 1.85 (1.56, 2.19) Non

• Black

1.85 (1.60, 2.14) Black 1.84 (1.51, 2.24) Women 1.78 (1.49, 2.14) Men 1.89 (1.62, 2.20) Age >= 65 1.89 (1.65, 2.17) Age < 65 1.76 (1.40, 2.22) Total 1.80 (1.61, 2.02) 0.33 0.50 1 2 3 No CHD 1.91 (1.64, 2.22) CHD 1.75 (1.46, 2.11) Treated 1.87 (1.66, 2.11) Untreated 1.54 (0.98, 2.42) Nondiabetic 1.88 (1.60, 2.20) Diabetic 1.85 (1.56, 2.19) Non

• Black

1.85 (1.60, 2.14) Black 1.84 (1.51, 2.24) Women 1.78 (1.49, 2.14) Men 1.89 (1.62, 2.20) Age >= 65 1.89 (1.65, 2.17) Age < 65 1.76 (1.40, 2.22) Total 1.80 (1.61, 2.02)

RR and 95% CI for Heart Failure

ALLHAT

Cumulative Stroke Rate Years to Stroke 1 2 3 4 5 .02 .04 .06 .08

Stroke Rates by ALLHAT Treatment Group

RR (95% CI) p value D/C 1.26 (1.10 – 1.46) 0.001

ALLHAT

Chlorthalidone Doxazosin

STROKE

Favors Doxazosin Favors Chlorthalidone 0.50

1.27 (1.07 - 1.52) 1.23 (0.96 - 1.58) 1.23 (1.06 - 1.43) 1.60 (0.99 - 2.59) 1.32 (1.09 - 1.60) 1.21 (0.98 - 1.51) 1.18 (0.98 - 1.42) 1.38 (1.10 - 1.73) 1.18 (0.94 - 1.49) 0.32 (0.10 - 1.59) 1.28 (1.08 - 1.51) 1.22 (0.93 - 1.61) Non-Diabetic No CHD CHD Treated Untreated Diabetic Non-Black Black Women Men Age>=65 Age<65 Total 1.26 (1.00 - 1.46)

1 2

ALLHAT

Cumulative CHD Event Rate Years to CHD Event 1 2 3 4 5 .03 .06 .09 .12

CHD Rates by ALLHAT Treatment Group

RR (95% CI) p value D/C 1.03 (0.92 – 1.15) 0.62

ALLHAT

Chlorthalidone Doxazosin

ALLHAT

CHD

Favors Doxazosin Favors Chlorthalidone 0.5 1.0 2.0 1.01 (0.87 - 1.17) 1.05 (0.88 - 1.25) 1.04 (0.92 - 1.17) 0.93 (0.63 - 1.36) 1.00 (0.87 - 1.16) 1.07 (0.91 - 1.27) 1.00 (0.88 - 1.15) 1.12 (0.90 - 1.36) 1.15 (0.94 - 1.39) 0.97 (0.85 - 1.11) 1.02 (0.89 - 1.17) 1.05 (0.86 - 1.27) 1.03 (0.92 - 1.15) Total Age<65 Age>=65 Men Women Black Non-Black Diabetic Non-Diabetic Untreated Treated CHD No CHD

Cumulative Mortality Rate Years to Death 1 2 3 4 5 .04 .08 .12 .16

All-Cause Mortality by ALLHAT Treatment Group

RR (95% CI) p value D/C 1.03 (0.94 – 1.13) 0.50

ALLHAT

Chlorthalidone Doxazosin

ALLHAT

TOTAL MORTALITY

Favors Doxazosin Favors Chlorthalidone 0.50 1 2 1.03 (0.93 - 1.15) 1.02 (0.88 - 1.20) 1.02 (0.93 - 1.12) 1.16 (0.86 - 1.55) 1.07 (0.95 - 1.20) 0.99 (0.86 - 1.14) 1.01 (0.90 - 1.14) 1.06 (0.92 - 1.22) 1.10 (0.95 - 1.27) 0.99 (0.88 - 1.11) 1.07 (0.97 - 1.19) 0.90 (0.75 - 1.09) 1.03 (0.84 - 1.13) Total Age<65 Age>=65 Men Women Black Non-Black Diabetic Non-Diabetic Untreated Treated CHD No CHD

Total Age<65 Age>=65 Men Women Black Non-Black Diabetic Non-diabetic Untreated Treated CHD No CHD

ALLHAT ESRD

Favors Doxazosin Favors Chlorthalidone 0.25 0.50 1 2 3 4 1.21 (0.84 - 1.76) 0.73 (0.41 - 1.32) 1.05 (0.76 - 1.44) 0.97 (0.29 - 3.33) 0.83 (0.51 - 1.35) 1.26 (0.84 - 1.88) 1.08 (0.70 - 1.67) 0.99 (0.63 - 1.55) 1.14 (0.71 - 1.85) 0.97 (0.65 - 1.44) 1.15 (0.79 - 1.68) 0.85 (0.49 - 1.48) 1.04 (0.84 – 1.76)

Biochemical Changes ALLHAT

Baseline 4 Years Chlor Dox Chlor Dox

Serum cholesterol, mg/dl 216 215 197 187 Serum potassium, mmol/l 4.3 4.4 4.1 4.4 Fasting serum glucose, mg/dl 123 122 125 117 Serum creatinine, mg/dl 1.0 1.0 1.2 1.1

Diabetes Incidence

ALLHAT

Chlorthalidone Doxazosin Difference (D-C) Number randomized 6755 3997 Baseline (n) 6755 3997 Mean (sd) mg/dL 93.1 (11.7) 93.0 (11.5)

• 0.1

>= 126 mg/dL, % 0.0 0.0 0.0 24 Months (n) 2598 1496 Mean (sd) mg/dL 102.3 (26.6) 97.1 (18.9)

• 5.2

Mean (sd) change 8.5 (24.4) 3.1 (17.7)

• 5.4

>= 126 mg/dL, % 9.5 4.7

• 4.8

48 Months (n) 773 467 Mean (sd) mg/dL 104.0 (29.4) 99.7 (25.1)

• 4.3

Mean (sd) change 9.2 (27.1) 5.1 (22.9)

• 4.1

>= 126 mg/dL, % 10.6 8.8

• 1.8

Final Results Confirm That for Doxazosin / Chlorthalidone:

• 20% ↑ risk of combined CVD
• 80% ↑ risk of heart failure
• 26% ↑ risk of stroke
• No difference for CHD or for total mortality

ALLHAT

Increased risk for some CV events for doxazosin in spite

• f lower total cholesterol and lower fasting glucose.

Conclusions

Chlorthalidone is superior to doxazosin for: ♥ Hypertension control ♥ Drug compliance ♥ Reduction of cardiovascular complications In addition, chlorthalidone is much less expensive

ALLHAT

Lessons Learned - 1

• For some drugs, BP lowering is an

inadequate marker (surrogate) of health benefits in hypertension

• Antihypertensive drugs can have

important non-BP actions that may alter the benefit of BP lowering

ALLHAT

Lessons Learned - 2

• Comparative outcome trials, like ALLHAT,

are essential for documenting optimal drug benefit / risk balance and for guiding the practice of medicine

• All major health outcomes of a treatment

should be evaluated

ALLHAT

Recommendations

• Chlorthalidone (diuretic) is the

recommended drug of choice for initial antihypertensive treatment in high risk hypertensive patients.

• Doxazosin is not recommended as first-

line therapy in hypertension.

ALLHAT

Additional Comments

• ALLHAT does not allow an assessment of

the effect of doxazosin compared with placebo on the incidence of CVD.

• The use of doxazosin as a step-up drug

for treating hypertension was not tested in this trial.

• These findings are likely to apply to all

alpha-blockers.

ALLHAT